Intranigral injection of Alpha-Synuclein pre-formed fibrils leads to BBB compromise and Bilateral Dopaminergic Neurodegeneration in A53T Alpha-Synuclein transgenic mice.

Ghosh, S.; Lin, H. H.; Chu, S.; Ngu, H.; Zang, N.; Raman, R.; Stark, K.; Foreman, O.; Hashemifar, S.; Easton, A.; Bingol, B.; Meilandt, W. J.

doi:10.1101/2025.11.26.690780

bioRxiv · 10.1101/2025.11.26.690780

Intranigral injection of Alpha-Synuclein pre-formed fibrils leads to BBB compromise and Bilateral Dopaminergic Neurodegeneration in A53T Alpha-Synuclein transgenic mice.

Ghosh, S.·Lin, H. H.·Chu, S.·Ngu, H.·Zang, N.·Raman, R.·Stark, K.·Foreman, O.·Hashemifar, S.·Easton, A.·Bingol, B.·Meilandt, W. J.

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Abstract

Parkinsons disease (PD) is a progressive neurodegenerative disorder characterized by alpha-()-Synuclein neuronal aggregation and loss of dopaminergic (DA) neurons. Developing animal models that replicate PDs neuropathological phenotypes is critical for understanding its pathophysiology and evaluating potential therapeutic targets. In this study, we show that direct unilateral injection of human -Synuclein PFFs into the Substantia Nigra (SN) of mutant A53T -synuclein overexpressing mice induce bilateral phosphorylated -Synuclein (pS129) pathology in the SN. This pathology spreads to the striatum, cerebral cortex, and midbrain within 60 days and is accompanied by neuroinflammation in the midbrain and cerebral cortex. Additionally, we observed synuclein-dependent neurodegeneration, with a 50% reduction in Tyrosine Hydroxylase (TH) intensity in the SN and a 40% reduction in Striatum, both bilaterally. The model also revealed a compromised blood-brain barrier (BBB) and T-cell infiltration in the PFF injected animals, correlating with pS129 pathology and neuroinflammation. Taken together, we developed a mouse model that recapitulates multiple PD phenotypes, providing a valuable platform for testing therapeutic strategies targeting human -Synuclein pathology and for exploring CNS-peripheral immune interactions in PD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/690780v2_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@19c6234org.highwire.dtl.DTLVardef@1f36bbaorg.highwire.dtl.DTLVardef@25ac6borg.highwire.dtl.DTLVardef@15ad61d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Ghosh, S., Lin, H. H., Chu, S., Ngu, H., Zang, N., Raman, R., Stark, K., Foreman, O., Hashemifar, S., Easton, A., Bingol, B., Meilandt, W. J.. 2025-12-01. Intranigral injection of Alpha-Synuclein pre-formed fibrils leads to BBB compromise and Bilateral Dopaminergic Neurodegeneration in A53T Alpha-Synuclein transgenic mice.. https://doi.org/10.1101/2025.11.26.690780

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